Atherosclerotic Cardiovascular Disease (ASCVD) is the most common cause of death in industrial countries (JAR, 150:1263-1269 (1988)). Peripheral Vascular Disease (PVD) also contributes to the morbidity and mortality rates in these populations. In both diseases, damage is mediated by an occlusive lesion of the involved vessel. This lesion is generically called a thrombus. A thrombus is an aggregate of elements formed on the wall of an involved vessel from constituents of the blood in response to a thrombogenic stimuli. This process of thrombus formation is termed thrombosis. Body tissues distal to the occlusion are deprived of their normal blood flow and its ensuing benefits.
Over the years various medical interventions have been employed to remove or otherwise treat an offending thrombotic lesion. Various surgical methods have also been used resulting in significant medical advancement. The surgical interventions include replacement of the aorta, and coronary artery by-pass grafting (CABG), the gold standard for treatment of lesions involving the coronary vessels of the heart. However, despite these procedures and their advancement in the treatment of this disease, a need continues to exist for treatment with less expensive and less invasive methods.
Percutaneous transluminal angioplasty (PTA). or balloon angioplasty, has proven to be a useful non-surgical procedure for the treatment of localized occlusive atherosclerotic lesions of both coronary and peripheral vessels (Merck Manual, 15th Ed., p. 559). This technique involves the cannulation of an affected vessel with a special catheter. An uninflated balloon portion of the catheter is introduced into the narrowed vessel lumen so that it is juxtapositioned to the lattice-like network of the forming thrombus. Inflation of the balloon portion of the catheter compresses the offending thrombus against the vessel wall thereby restoring lumen patency. The balloon is then typically deflated and the catheter is withdrawn.
Following PTA, blood flow through the artery is usually significantly improved. Unfortunately, however, although more than 90% of the balloon dilations are initially successful, there is a high rate (35-40%) of late restenosis. Longer balloon inflation times, high doses of calcium-channel blockers, steroids, and other drug regimens have been attempted but so far have proved unsuccessful in combating this problem (NEJM, 316:701 (1987)). Indeed, about one-third of all patients treated with PTA return for a second or third procedure, thus reducing the long-term benefits of the procedure (Eur. Heart J., 9:31-37 (1988)). A need exists therefore, for a method to increase the long-term benefits of PTA, with the aim of preventing restenosis of the diseased vessel.
Vessels of the human body are lined by a smooth surface known as the endothelium. The innermost layer of the endothelium is called the intima. This impervious layer improves vascular bloodflow hemodynamics and shields deeper vessel wall layers from contact with the blood itself. Unfortunately, successful PTA invariably involves some interruption of this lining with a resulting violation of the barrier it provides between the deeper placed smooth muscle cells (SMC) of the vessel wall and the blood itself. Local hemodynamic flow characteristics are also affected. It is some combination of these two factors that leads to a later recurrence of partial vessel occlusion in 35-40% of otherwise successful PTA procedures.
With regard to the SMC, one mechanism of vessel restenosis is SMC hyperplasia. In histologic sequences that resemble tumor growth, the vessel SMCs dedifferentiate from a contractile to a synthetic phenotype, followed by intense proliferation and the production of connective tissue. In an attempt to prevent this cell proliferation and post-angioplasty restenosis, we reported the systemic administration of antitumor cytostatic agents which would selectively damage active and proliferating smooth muscle cells (JACC 13(2):252A (1989)). Systemically administered drugs such as anticoagulants and vasodilators have so far proven ineffective to prevent restenosis. More radical treatment involving agents such as cytostatic drugs or general enzyme blockers may prevent smooth muscle cell proliferation but often these agents are toxic to humans at the levels necessary to effectively block development of the involved pathology. As with many systemically administered drugs, the chief complication is the adverse effects or toxicities on normal cells. For that reason, the inventors have proposed local administration of such agents. In particular, cytotoxic antitumor agents are suggested as a means of selectively damaging the hyperplastic SMCs.
Problems remain, however, in the exact method by which this local administration should be accomplished. The conventional methods of drug therapy, including tablets, capsules, slow-release formulations and injectables, all result in typical fluctuations of drug concentrations at the target site. With every dose of the drug, serum concentrations may alternatively reach levels that produce adverse side effects and then decline to values significantly less than therapeutic. As a result, in order to be effective, potent agents destined to treat specific sites must travel through the bloodstream in much larger concentrations than those required at the target (Med. Res. Rev., 1(4):373-386 (1981)). Even with local administration of these agents, the normal blood flow of the vessel will dilute the local concentration of the therapeutic agent by a wash-out effect. A need exists therefore, for a method of preventing restenosis that assures adequate therapeutic effect while reducing or eliminating toxic side effects. A need also exists for a system whereby otherwise toxic therapeutic agents are concentrated and localized within the affected vessel wall segment. The present invention satisfies these needs and provides related advantages as well.